Extended release suspension compositions

ABSTRACT

The present invention relates to a method for preparing a stable extended release suspension composition comprising multiple coated cores of an active ingredient by using a suspension base, wherein the suspension base ensures substantially similar in-vitro dissolution release profile of the active ingredient upon storage of the suspension compositions for at least seven days.

FIELD OF THE INVENTION

The present invention relates to a method for preparing a stableextended release suspension composition comprising multiple coated coresof an active ingredient by using a suspension base, wherein thesuspension base ensures substantially similar in-vitro dissolutionrelease profile of the active ingredient upon storage of the suspensioncompositions for at least seven days.

BACKGROUND OF THE INVENTION

Extended release solid compositions are preferred dosage forms overimmediate release solid compositions, especially for active ingredientsshowing fluctuations in the plasma concentration and for activeingredients having short half-lives. Extended release solid compositionscan be in the form of tablets or capsules, wherein the release of theactive ingredient is controlled by using a reservoir or a matrix system.However, extended release solid oral compositions suffer from certaindrawbacks such as difficulty in swallowing, particularly for certaingroups of patients, e.g., pediatrics and geriatrics, resulting in poorpatient compliance. Further, high doses of active ingredient lead tolarge-sized compositions which aggravates this problem. Also, thereremains a tendency to divide extended release solid compositions such astablets into small pieces in order to facilitate administration, whichmay ultimately lead to inaccurate dosing and/or dose dumping. In view ofall this, extended release liquid compositions provide the bestalternative over extended release solid compositions. Extended releaseliquid compositions are easy to administer, thereby leading to enhancedpatient compliance. Additionally, extended release liquid compositionsprovide a unique advantage of having a flexible dosing regimen.

Although extended release liquid compositions are advantageous, thereremain some complexities involved in formulating such compositions. Theimportant prerequisite of these compositions is to provide the desiredextended release of the active ingredient throughout its shelf life, asirregular release may lead to sub-therapeutic or toxic effects. The keyhurdle remains to overcome the leaching of the active ingredient fromthe coated cores into a suspension base during storage. The objectivefor a scientist remains to develop a formulation such that the releaseof the active ingredient into the suspension base during storage isavoided, and only when the suspension enters the gastrointestinal tractthe release is allowed.

The prior art discloses various approaches to overcome the leachingproblem for the preparation of extended release liquid compositions.

PCT Publication No. WO 2012/063257 and U.S. Publication No. 2008/0118570disclose extended release suspensions employing ion-exchange resins.Although ion-exchange resin systems provide the desired extended releaseof the active ingredient without significant leaching during storage,these systems require chemical binding of the active ingredient to theresin, which is complicated and not suitable for many activeingredients.

PCT Publication No. WO 2011/107855 discloses a ready to use sustainedrelease oral suspension comprising inert pellets surrounded by a sealcoating, an active ingredient layer surrounding the seal coated inertpellets, and a coating layer comprising a rate-controlling polymersurrounding the active ingredient layer. Said sustained release pelletsare further coated with a protective coating layer which prevents theleaching of the active ingredient.

PCT Publication No. WO 2008/122993 discloses a suspension of an activeingredient containing microparticles with at least one coat of apH-independent polymer. Further, there is an additional coat ofpH-dependent polymer which provides stability to the formulation byavoiding leaching of active ingredient in the liquid phase afterreconstitution during storage.

In the formulations disclosed in these prior art, the leaching of theactive ingredients from the coated units into the media during storageis primarily prevented by the use of a multiple coating systems.However, the process of applying multiple coating systems remainstime-consuming, complicated, and difficult to be functionallyreproducible.

U.S. Pat. No. 7,906,145 discloses a sustained release suspensioncomprising microcapsules suspended in an aqueous liquid phase saturatedwith an active ingredient, wherein each microcapsule comprises a core ofthe active ingredient and a coating layer applied to the core whichcontrols the modified release of the active ingredient ingastrointestinal fluids. Said coating layer comprises a film-formingpolymer, a nitrogen-containing polymer, a plasticizer, and asurfactant/lubricant. The coating layer is designed in a way such thatthe release profile is not perturbed in the liquid phase and the activeingredient contained in the microcapsules is prevented from escapinginto the liquid phase throughout the storage of the suspension. However,this system also requires mandatory use of an aqueous phase saturatedwith the active ingredient which may not be suitable for activeingredients having low aqueous solubility and/or low dose. Further, thissystem is limited to class of active ingredients which require animmediate dose or an initial spike in the release profile and thereforeis not suitable for active ingredients which do not require anyimmediate dose of the active ingredient. Also, the aqueous phasesaturated with the active ingredient remains physically unstable as asmall variation in temperature, pH, and/or ionic concentration may leadto salting out or precipitation of the active ingredient.

In view of all these, there remains a need in the art to formulateextended release suspension compositions of the active ingredients whichare based on a simplified and robust technology and which providesignificant advancement over the existing prior art. The extendedrelease suspension compositions of the present invention are suitablefor variety of active ingredients including active ingredients havinglow aqueous solubility or active ingredients which do not require anyimmediate dose of the active ingredient. The extended release suspensioncompositions of the present invention remain physically stable to anyvariation in temperature, pH, and/or ionic concentration. Furthermore,the extended release suspension compositions of the present inventionprovide the desired extended release throughout the shelf life of thecompositions.

The present invention provides extended release suspension compositionsbased on a simplified technology, prepared by a process which isrelatively simple, easy to commercially manufacture, and functionallyreproducible. The present invention uses a unique suspension base whichprevents the leaching of the active ingredient from the coated coresduring storage. The suspension base thus ensures substantially similarin-vitro dissolution release profile of the active ingredient uponstorage throughout the shelf life of the compositions. This consistentin-vitro release then ensures a steady plasma concentration with nofluctuations throughout the shelf life of the compositions.Additionally, the extended release suspension compositions of thepresent invention are able to incorporate two or more active ingredientswith different release profiles or two or more incompatible activeingredients in a single composition.

SUMMARY OF THE INVENTION

The present invention relates to a method for preparing a stableextended release suspension composition comprising multiple coated coresof an active ingredient by using a suspension base, wherein thesuspension base ensures substantially similar in-vitro dissolutionrelease profile of the active ingredient upon storage of the suspensioncomposition for at least seven days.

The extended release suspension composition of the present invention iseasy to administer, thereby leading to enhanced patient compliance.Further, said extended release suspension composition provides betterdose flexibility depending on the age and body weight of the patient.Also, said extended release suspension composition is stable, easy tocommercially manufacture, and provide reproducible bioavailability.Additionally, said extended release suspension composition provides apleasant mouth feel and taste masking for bitter drugs, thereby furtherenhancing patient compliance. The present invention provides suchcomposition and improves patient compliance by reducing dosing frequencyfor pediatric as well as geriatric patients.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the in-vitro dissolution release on day 0, day 30, and day66 of the extended release suspension composition prepared according toExample 4 upon storage at room temperature. This figure also shows thein-vitro dissolution release on day 0, day 36, and day 66 of theextended release suspension composition (at room temperature) formedafter reconstituting the powder stored for one month at acceleratedconditions.

FIG. 2 shows the in-vitro dissolution release on day 0 and day 30 of theextended release suspension composition prepared according to Example 5upon storage at room temperature. This figure also shows the in-vitrodissolution release on day 0 and day 32 of the extended releasesuspension composition (at room temperature) formed after reconstitutingthe powder stored for three months and six months at acceleratedconditions.

FIG. 3 shows the in-vitro dissolution release on day 0 and day 30 of theextended release suspension composition prepared according to Example 6upon storage at room temperature. This figure also shows the in-vitrodissolution release on day 0 and day 30 of the extended releasesuspension composition (at room temperature) formed after reconstitutingthe powder stored for one month at accelerated conditions.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention provides a method for preparinga stable extended release suspension composition comprising multiplecoated cores of an active ingredient by using a suspension base, whereinthe suspension base ensures substantially similar in-vitro dissolutionrelease profile of the active ingredient upon storage of the suspensioncomposition for at least seven days.

According to one embodiment of the above aspect, the suspension base ischaracterized by having the features of:

a viscosity in a range of about 500 cps to about 15,000 cps; and

(ii) an osmolality of at least about 1 osmol/kg of the suspension base.

According to another embodiment of the above aspect, the suspension basecomprises:

a suspending agent;

(ii) an osmogent; and

(iii) an aqueous vehicle.

According to another embodiment of the above aspect, the suspension basedoes not include a saturated solution of the active ingredient.

According to another embodiment of the above aspect, the suspension basegenerates a hypertonic condition such that there is no substantialchange in the in-vitro dissolution release profile of the activeingredient upon storage of the extended release suspension compositionfor at least seven days.

According to another embodiment of the above aspect, the stable extendedrelease suspension composition is characterized by having an osmolalityratio of at least about 1.

According to another embodiment of the above aspect, the coated corecomprises a core of the active ingredient and a coating layer over saidcore comprising one or more release-controlling agents.

According to another embodiment of the above aspect, the core of theactive ingredient is in the form of a bead, a pellet, a granule, aspheroid, or the like.

According to another embodiment of the above aspect, the activeingredient is layered onto an inert particle to form the core.

According to another embodiment of the above aspect, the inert particleis selected from the group comprising a non-pareil seed, amicrocrystalline cellulose sphere, a dibasic calcium phosphate bead, amannitol bead, a silica bead, a tartaric acid pellet, a sugar bead, or awax based pellet.

According to another embodiment of the above aspect, the averagediameter of the coated cores ranges from about 10 μm to about 2000 μm.In a preferred embodiment, the average diameter of the coated coresranges from about 50 μm to about 1000 μm. In a more preferredembodiment, the average diameter of the coated cores ranges from about150 μm to about 500 μm.

According to another embodiment of the above aspect, the stable extendedrelease suspension composition is a taste-masked composition.

According to another embodiment of the above aspect, the stable extendedrelease suspension composition is in the form of a suspension or areconstituted powder for suspension.

According to another embodiment of the above aspect, therelease-controlling agent is selected from the group comprising apH-dependent release-controlling agent, a pH-independentrelease-controlling agent, or mixtures thereof.

A second aspect of the present invention provides a process for thepreparation of a stable extended release suspension composition, whereinthe process comprises the steps of:

-   -   (i) preparing cores comprising an active ingredient and one or        more pharmaceutically acceptable excipients;    -   (ii) dissolving/dispersing a release-controlling agent and one        or more pharmaceutically acceptable coating additives in a        suitable solvent;    -   (iii) applying the coating composition of step (ii) over the        cores of step (i);    -   (iv) dissolving/dispersing one or more suspending agents, one or        more osmogents, and optionally one or more pharmaceutically        acceptable excipients into an aqueous vehicle to form a        suspension base; and    -   (v) dispersing the coated cores of step (iii) in the suspension        base of step (iv) to obtain the stable extended release        suspension composition.

A third aspect of the present invention provides a process for thepreparation of a stable extended release suspension composition, whereinthe process comprises the steps of:

-   -   (A) preparing a powder for suspension comprising the steps of:        -   (i) preparing cores comprising an active ingredient and one            or more pharmaceutically acceptable excipients;        -   (ii) dissolving/dispersing a release-controlling agent and            one or more pharmaceutically acceptable coating additives in            a suitable solvent;        -   (iii) applying the coating composition of step (ii) over the            cores of step (i);        -   (iv) mixing one or more pharmaceutically acceptable            excipients with the coated cores of step (iii) to obtain the            powder for suspension;    -   (B) preparing a suspension base by dissolving/dispersing one or        more suspending agents, one or more osmogents, and optionally        one or more pharmaceutically acceptable excipients into an        aqueous vehicle; and    -   (C) reconstituting the powder for suspension of step (A) with a        suspension base of step (B) to obtain the extended release        suspension composition.

A fourth aspect of the present invention provides a process for thepreparation of a stable extended release suspension composition, whereinthe process comprises the steps of:

-   -   (A) preparing a powder for suspension comprising the steps of:        -   (i) preparing cores comprising an active ingredient and one            or more pharmaceutically acceptable excipients;        -   (ii) dissolving/dispersing a release-controlling agent and            one or more pharmaceutically acceptable coating additives in            a suitable solvent;        -   (iii) applying the coating composition of step (ii) over the            cores of step (i);        -   (iv) mixing one or more suspending agents, one or more            osmogents and optionally one or more pharmaceutically            acceptable excipients with the coated cores of step (iii) to            obtain the powder for suspension; and    -   (B) reconstituting the powder for suspension of step (A) with an        aqueous vehicle to obtain the extended release suspension        composition.

The term “extended release,” as used herein, refers to the releaseprofile of the active ingredient over an extended period of time, e.g.,over a period of 4, 6, 8, 12, 24 hours, or more.

The term “osmolality ratio,” as used herein, means the ratio of theosmolality of the external phase to the osmolality of the internalphase. The external phase herein, means the suspension base withoutmultiple coated cores of the active ingredient. The internal phaseherein means the coated cores of the active ingredient. As the directmeasurement of the osmolality of the internal phase i.e., coated coresis difficult, the osmolality of the internal phase herein, isrepresented as the osmolality of a solution which prevents significantleaching of the active ingredient from the coated cores into thesolution. The leaching of the active ingredient from the coated cores isdetermined by the difference in the osmolalities across the coatinglayer and the absence of any significant leaching from the coated coresdirects that the osmolality of the solution has become equal to theosmolality of the coated cores. The osmolality ratio of the extendedrelease suspension compositions of present invention is at least about1.

The term “hypertonic condition,” as used herein, means the suspensionbase has higher solute concentration which helps to generate highosmotic pressure such that there is no leaching of the active ingredientfrom the coated cores into the suspension base. In the presentinvention, the solutes are osmogents i.e., pharmaceutically acceptableinert water-soluble compounds that contribute towards generatinghypertonic conditions in the suspension base.

The term “osmolality,” as used herein, is expressed as number of molesof any water-soluble compound per kg of a liquid phase. The liquid phasecan be a suspension base or a solution. In the present invention, theosmolality may be measured according to known methods, such as using avapor pressure osmometer, a colloid osmometer, or a freezing pointdepression osmometer such as Osmomat® 030-D or Osmomat® 3000, inparticular by a freezing point depression osmometer. The suspension baseof the present invention has an osmolality of at least about 1 osmol/kgof the suspension base. In particular, the suspension base of thepresent invention has an osmolality of at least about 2 osmol/kg of thesuspension base. The suspension base of the present invention has anosmolality ranging from about 1 osmol/kg to about 20 osmol/kg of thesuspension base.

The osmolality of the suspension base of the extended release suspensioncompositions of the present invention remains equivalent upon storagefor at least seven days. Particularly, the osmolality of the suspensionbase measured after one month remains equivalent to the osmolality ofthe suspension base measured as soon as practicable after preparation ofthe extended release suspension compositions. More particularly, theosmolality of the suspension base measured after three months or sixmonths remains equivalent to the osmolality of the suspension basemeasured as soon as practicable after preparation of the extendedrelease suspension compositions. The equivalent osmolality of thesuspension base ensures that there is no leaching of the activeingredient from the coated cores into the suspension base.

The viscosity of the suspension base of the present invention rangesfrom about 500 cps to about 15,000 cps. Preferably, the viscosity of thesuspension base ranges from about 1,000 cps to about 10,000 cps. Morepreferably, the viscosity of the suspension base ranges from about 2,000cps to about 7,000 cps. The viscosity of the suspension base of thepresent invention is measured by using a Brookfield Viscometer having a#2 spindle rotating at 5 rpm at 25° C.

The term “stable,” as used herein, refers to chemical stability, whereinnot more than 5% w/w of total related substances are formed on storageat 40° C. and 75% relative humidity (R.H.) or at 25° C. and 60% R.H. fora period of at least three months to the extent necessary for the saleand use of the composition.

The term “inert particle,” as used herein, refers to a particle madefrom a sugar sphere also known as a non-pareil seed, a microcrystallinecellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, asilica bead, a tartaric acid pellet, a wax based pellet, and the like.

The term “about,” as used herein, refers to any value which lies withinthe range defined by a variation of up to ±10% of the value.

The term “equivalent” as used herein, refers to any value which lieswithin the range defined by a variation of up to ±30% of the value.

The term “significant leaching,” as used herein means more than 20% ofthe active ingredient is leached out from the coated cores into thesolution.

The in-vitro dissolution release profile of the extended releasesuspension composition of the present invention upon storage for atleast seven days remains substantially similar to the initial in-vitrodissolution release profile obtained as soon as practicable afterpreparation of the extended release suspension composition.Particularly, the in-vitro dissolution release profile of the extendedrelease suspension composition of the present invention upon storage forat least one month remains substantially similar to initial in-vitrodissolution release profile obtained as soon as practicable afterpreparation of the extended release suspension composition. Moreparticularly, the in-vitro dissolution release profile of the extendedrelease suspension composition of the present invention upon storage forat least three months remains substantially similar to initial in-vitrodissolution release profile obtained as soon as practicable afterpreparation of the extended release suspension compositions. Moreparticularly, the in-vitro dissolution release profile of the extendedrelease suspension composition of the present invention upon storage forat least six months remains substantially similar to initial in-vitrodissolution release profile obtained as soon as practicable afterpreparation of the extended release suspension composition. In thepresent invention, wide ranges of dissolution methodologies can beutilized for different active ingredients. These methodologies can beadopted to vary in hydrodynamic mechanism to simulate in-vivo conditionsby using different dissolution apparatuses, volume of media, pH of mediaranging from 1.0 to 7.5, any standard USP buffers with standardmolarity, addition of surfactants, and or enzymes.

The extended release suspension composition of the present inventionprovides the consistent in-vivo release which ensures steady andpredictable active ingredient release with minimal inter and intrasubject variation throughout the shelf life of the composition.

The term “substantial,” as used herein refers to any value which lieswithin the range as defined by a variation of up to ±15 from the averagevalue.

The term “suspension base,” as used herein, refers to a medium which isused to suspend the coated cores of the active ingredient. Thesuspension base of the present invention is characterized by having aviscosity in a range of about 500 cps to about 15,000 cps; and anosmolality of at least about 1 osmol/kg of the suspension base.

The suspension base generates a hypertonic condition such that there isno substantial change in the in-vitro dissolution release profile of theactive ingredient upon storage of the suspension composition for atleast seven days. Alternatively, the suspension base may have a pH suchthat there is no substantial change in the in-vitro dissolution releaseprofile of the active ingredient upon storage of the suspensioncomposition for at least seven days. In this case, the active ingredientmay have a pH-dependent solubility and the pH of the suspension base isadjusted to a pre-determined pH at which the active ingredient remainssubstantially insoluble.

The extended release suspension composition of the present invention maybe in the form of a suspension or a reconstituted powder for suspension.

The suspension base of the present invention comprises one or moresuspending agents, one or more osmogents, and an aqueous vehicle. It mayfurther comprise one or more pharmaceutically acceptable excipients. Thepowder for suspension having coated cores of active ingredient of thepresent invention may be reconstituted with the suspension base havingsuspending agents, osmogents, pharmaceutically acceptable excipients,and an aqueous vehicle. Alternatively, suspending agents, osmogents, orother pharmaceutically acceptable excipients may be premixed with thecoated cores which may be reconstituted with an aqueous vehicle. In caseof powder for suspension, the suspension base may be pre-formed orformed at the time of reconstitution.

The aqueous vehicle may comprise of purified water or a mixture ofpurified water with one or more suitable organic solvents.

The average diameter of the coated cores of the present invention rangesfrom about 10 μm to about 2000 μm, particularly from about 50 μm toabout 1000 μm, and more particularly from about 150 μm to about 500 μm.The finer sizes of the coated cores help in avoiding grittiness in themouth and are therefore more acceptable. The cores of the presentinvention may comprise one or more pharmaceutically acceptableexcipients such as a binder, a release-controlling agent, an osmogent, astabilizer, a solubilizer, or a pH modifying agent. The stabilizer mayinclude but not limited to a pH modifying agent, a chelating agent, oran anti-oxidant. The solubilizer may include but not limited to asolubility enhancing agent, a pH modifying agent, an adsorbent, or acomplexing agent.

The active ingredient of the present invention includes any activeingredient belonging to a therapeutic category, including but notlimited to antidiabetic, antibiotic, antimicrobial, analgesic,antiallergic, antianxiety, antiasthmatic, anticancer, antidepressant,antiemetic, antiinflammatory, anti-Parkinson's, antiepileptic,antitussive, antiviral, immunosuppressant, diuretic, antimigraine,antihypertensive, hypolipidemics, anti-arrhythmics, vasodilators,anti-anginals, sympathomimetic, cholinomemetic, adrenergic,antimuscarinic, neuroleptics, antispasmodic, skeletal muscle relaxants,expectorants, and drugs for treating attention deficit hyperactivedisorder. The active ingredient of the present invention can be presentin the form of a free base or in the form of pharmaceutically acceptablesalts. Specific examples of active ingredients include but are notlimited to the group comprising metformin, acarbose, miglitol,voglibose, repaglinide, nateglinide, glibenclamide, glimepride,glipizide, gliclazide, chloropropamide, tolbutamide, phenformin,aloglitin, sitagliptin, linagliptin, saxagliptin, rosiglitazone,pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone,isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar,tesaglitazar, canagliflozin, dapagliflozin, remogliflozin, sergliflozin,verapamil, albuterol, salmeterol, acebutolol, sotalol, penicillamine,norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin,trovafloxacin, gatifloxacin, cefixime, cefdinir, cefprozil, cefadroxil,cefuroxime, cefpodoxime, tetracycline, demeclocycline hydrochloride,amoxicillin, clavulanate potassium, azithromycin, losartan, irbesartan,eprosartan, valsartan, diltiazem, isosorbide mononitrate, ranolazine,propafenone, hydroxyurea, hydrocodone, delavirdine, pentosanpolysulfate, abacavir, amantadine, acyclovir, ganciclovir, valacyclovir,valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine,didanosine, zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen,propoxyphene, cimetidine, ranitidine, albendazole, mebendazole,thiobendazole, pyrazinamide, praziquantel, chlorpromazine, sumatriptan,bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride,niacin, tocainide, quetiapine, fexofenadine, sertraline,chlorpheniramine, rifampin, methenamine, nefazodone, modafinil,metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate,simethicone, methyldopa, chlorthiazide, metyrosine, procainamide,entacapone, metoprolol, propanolol hydrochloride, chlorzoxazone,tolmetin, tramadol, bepridil, phenytoin, gabapentin, fluconazole,terbinafine, atorvastatin, doxepine, rifabutin, mesalamine, etidronate,nitrofurantoin, choline magnesium trisalicylate, theophylline,nizatidine, methocarbamol, mycophenolate mofetil, tolcapone,ticlopidine, capecitabine, orlistat, colsevelam, meperidine,hydroxychloroquine, guaifenesin, guanfacine, amiodarone, quinidine,atomoxetine, felbamate, pseudoephedrine, carisoprodol, venlafaxine,etodolac, chondrotin, lansoprazole, pantoprazole, esomeprazole,dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate,valproic acid or its salts, divalproex, topiramate, carbamazepine,oxcarbazepine, and isotretinoin. The dose of any active ingredientdepends upon the individual active ingredient used in the extendedrelease suspension compositions of the present invention. Further, theextended release suspension compositions of the present invention permitready dose titration, i.e., adjusting the dose of the active ingredientbased on recommended dose range and frequency until the desiredtherapeutic effect is achieved. In particular, the active ingredientsused in the present invention are active ingredients with a high dose.

The suspension base may additionally include an immediate releasecomponent of the active ingredient. However, the suspension base of thepresent invention does not include any saturated solution of the activeingredient. The suspension base may include an immediate releasecomponent of the active ingredient, wherein the active ingredient ispresent in an amount that does not exceed the amount required to formthe saturated solution either initially or during storage. The activeingredient may be present in the form of a powder, a pellet, a bead, aspheroid, or a granule, or in the form of immediate release coating overthe extended release coated cores. Alternatively, the amount of activeingredient may exceed the amount required to form the saturatedsolution. However, the saturated solution of active ingredient is notformed, as the release of active ingredient into the suspension base isprevented during storage. This is achieved by using a coating layer overthe cores of the active ingredient, wherein the coating layer comprisesa polymer that remain insoluble in the suspension base during storageand which releases the active ingredient in the immediate release formonce ingested. Alternatively, this can also be done by using acomplexation approach such as an ion-exchange resin complex, wherein thecomplex prevents any release of the active ingredient into thesuspension base during storage, and releases the active ingredient onlywhen exposed to the physiological conditions upon ingestion. The polymercan be a water-soluble polymer in which the release of active ingredientis prevented by using a high molar concentration of the solutes in thesuspension base, wherein the solutes have a higher affinity towardswater in comparison to the polymer. Further, the polymer can be having apH-dependent solubility in which the release of active ingredient isprevented by using a pre-adjusted pH of the suspension base such thatthe polymer does not get dissolved in the suspension base but getdissolved when exposed to the physiological conditions. For instance,acrylic polymers available under the trade mark Eudragit® E andEudragit® EPO are soluble at an acidic pH. The pH of the suspension basecan be pre-adjusted to a basic pH such that the coating does not getdissolved during storage but get dissolved in the stomach when ingested.

The immediate release component may help in providing an immediatetherapeutic effect which could be subsequently followed by an extendedtherapeutic effect over a longer duration of time once ingested.Depending upon the type of polymer and percentage weight gain of thecoating, the lag between the two phases can be adjusted to get thedesired release profile.

Further, the extended release suspension composition of the presentinvention may comprise two or more similar or different activeingredients with different type of release profiles.

The extended release suspension composition of the present invention mayalso comprise two or more incompatible active ingredients present in asingle composition. One of the active ingredients would be present inthe form of coated cores providing the extended release and anotherincompatible active ingredient may be present in the form of a powder, apellet, a bead, a spheroid, or a granule providing the immediate releaseor the extended release.

The extended release suspension compositions of the present inventionare homogeneous which means the compositions provide the contentuniformity and deliver the desired dose of the active ingredient inevery use without any risk of overdosing or underdosing.

The release-controlling agents used to form the extended release coatingare selected from a group comprising a pH-dependent release-controllingagent, a pH-independent release-controlling agent, or mixtures thereof.For an extended release coating comprising a pH-dependentrelease-controlling agent, the pH of the suspension base is pre-adjustedsuch that the coating remains insoluble in the suspension base duringthe storage. The extended release coating comprising a pH-dependentrelease-controlling agent may alternatively be coated with a coatinglayer comprising a polymer such that said coating layer remain insolublein the suspension base during storage. The core may compriserelease-controlling agents in the form of a matrix with the activeingredient, which can be coated with a coating layer that remaininsoluble in the suspension base during storage.

Suitable examples of pH-dependent release-controlling agent are selectedfrom the group comprising acrylic copolymers such as methacrylic acidand methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit®S 100, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® L100-55 and Eudragit® L 30 D-55, dimethylaminoethyl methacrylate andbutyl methacrylate and methyl methacrylate copolymers e.g., Eudragit® E100, Eudragit® E PO, methyl acrylate and methacrylic acid and octylacrylate copolymers, styrene and acrylic acid copolymers, butyl acrylateand styrene and acrylic acid copolymers, and ethylacrylate-methacrylicacid copolymer; cellulose acetate phthalate; cellulose acetatesuccinates; hydroxyalkyl cellulose phthalates such ashydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetatesuccinates such as hydroxypropylmethyl cellulose acetate succinate;vinyl acetate phthalates; vinyl acetate succinate; cellulose acetatetrimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate,polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinylacetoacetal phthalate; zein; shellac; and mixtures thereof.

Suitable examples of pH-independent release-controlling agent areselected from the group comprising cellulosic polymers such as ethylcellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose,and carboxy methylcellulose; acrylic copolymers such as methacrylic acidcopolymers, e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE 30 D;cellulose acetate; polyethylene derivatives e.g., polyethylene glycoland polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums e.g.,guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gumacacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes,e.g., Compritol®, Lubritab®, and Gelucires®; lipids; fatty acids ortheir salts/derivatives; a mixture of polyvinyl acetate and polyvinylpyrrolidone, e.g., Kollidon® SR; and mixtures thereof.

The term “osmogent,” as used herein, refers to all pharmaceuticallyacceptable inert water-soluble compounds that can imbibe water and/oraqueous biological fluids. Suitable examples of osmogents orpharmaceutically acceptable inert water-soluble compounds are selectedfrom the group comprising carbohydrates such as xylitol, mannitol,sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose,galactose, sucrose, maltose, lactose, dextrose and raffinose;water-soluble salts of inorganic acids such as magnesium chloride,magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride,potassium chloride, lithium hydrogen phosphate, sodium hydrogenphosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate,sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodiumphosphate tribasic; water-soluble salts of organic acids such as sodiumacetate, potassium acetate, magnesium succinate, sodium benzoate, sodiumcitrate, and sodium ascorbate; water-soluble amino acids such asglycine, leucine, alanine, methionine; urea or its derivatives;propylene glycol; glycerin; polyethylene oxide; xanthan gum;hydroxypropylmethyl cellulose; and mixtures thereof. Particularly, theosmogents used in the present invention are xylitol, mannitol, glucose,lactose, sucrose, and sodium chloride.

Suitable suspending agents are selected from the group comprisingcellulose derivatives such as co-processed spray dried forms ofmicrocrystalline cellulose and carboxymethyl cellulose sodium,hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethyl cellulose and itssalts/derivatives, and microcrystalline cellulose; carbomers; gums suchas locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum,agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum,acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin;polyethylene glycols; polyvinyl compounds such as polyvinyl acetate,polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such asxylitol and mannitol; colloidal silica; and mixtures thereof.Co-processed spray dried forms of microcrystalline cellulose andcarboxymethyl cellulose sodium have been marketed under the trade namesAvicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel® CL-611. Thesuspending agent is present in an amount of not more than about 20% w/w,based on the total weight of the suspension base.

The term “pharmaceutically acceptable excipients,” as used herein,refers to excipients that are routinely used in pharmaceuticalcompositions. The pharmaceutically acceptable excipients may compriseglidants, sweeteners, anti-caking agents, wetting agents, preservatives,buffering agents, flavoring agents, anti-oxidants, chelating agents,solubility enhancing agents, pH modifying agents, adsorbents, complexingagents, and combinations thereof.

Suitable glidants are selected from the group comprising silica, calciumsilicate, magnesium silicate, colloidal silicon dioxide, cornstarch,talc, stearic acid, magnesium stearate, calcium stearate, sodium stearylfumarate, hydrogenated vegetable oil, and mixtures thereof.

Suitable sweeteners are selected from the group comprising saccharine orits salts such as sodium, potassium, or calcium, cyclamate or its salt,aspartame, alitame, acesulfame or its salt, stevioside, glycyrrhizin orits derivatives, sucralose, and mixtures thereof.

Suitable anti-caking agents are selected from the group comprisingcolloidal silicon dioxide, tribasic calcium phosphate, powderedcellulose, magnesium trisilicate, starch, and mixtures thereof.

Suitable wetting agents are selected from the group comprising anionic,cationic, nonionic, or zwitterionic surfactants, or combinationsthereof. Suitable examples of wetting agents are sodium lauryl sulphate;cetrimide; polyethylene glycols; polyoxyethylene-polyoxypropylene blockcopolymers such as poloxamers; polyglycerin fatty acid esters such asdecaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fattyacid esters such as sorbitan monostearate; polyoxyethylene sorbitanfatty acid esters such as polyoxyethylene sorbitan monooleate;polyethylene glycol fatty acid esters such as polyoxyethylenemonostearate; polyoxyethylene alkyl ethers such as polyoxyethylenelauryl ether; polyoxyethylene castor oil; and mixtures thereof.

Suitable preservatives are selected from the group comprising parabenssuch as methyl paraben and propyl paraben; sodium benzoate; and mixturesthereof.

Suitable buffering agents are selected from the group comprising citricacid, sodium citrate, sodium phosphate, potassium citrate, acetatebuffer, and mixtures thereof.

Suitable flavoring agents are selected from the group consisting ofpeppermint, grapefruit, orange, lime, lemon, mandarin, pineapple,strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach,apricot, cherry, grape, banana, cranberry, blueberry, black currant, redcurrant, gooseberry, lingon berries, cumin, thyme, basil, camille,valerian, fennel, parsley, chamomile, tarragon, lavender, dill,bargamot, salvia, aloe vera balsam, spearmint, eucalyptus, andcombinations thereof.

Suitable anti-oxidants are selected from the group comprising butylatedhydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodiummetabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols,beta-carotene, and mixtures thereof.

Suitable chelating agents are selected from the group comprisingethylenediamine tetraacetic acid or derivatives/salts thereof, e.g.,disodium edetate; dihydroxyethyl glycine; glucamine; acids, e.g., citricacid, tartaric acid, gluconic acid, and phosphoric acid; and mixturesthereof.

Suitable binders are selected from the group comprising polyvinylpyrrolidone, starch, pregelatinized starch, hydroxypropylmethylcellulose, hydroxyethyl cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, gums, acrylate polymers, and mixtures thereof.

Suitable pH modifying agents are selected from the group comprisingfumaric acid, citric acid, tartaric acid, oxalic acid, malic acid,maleic acid, succinic acid, ascorbic acid, pyruvic acid, malonic acid,glutaric acid, adipic acid, gluconic acid, lactic acid, aspartic acid,sulfamic acid, sodium hydrogen carbonate, potassium hydrogen carbonate,sodium carbonate, potassium carbonate, magnesium carbonate, and calciumcarbonate, and mixtures thereof.

Suitable solubility enhancing agents are selected from the groupcomprising surfactants such as nonionic e.g., polyoxyethylene sorbitanfatty acid esters, sorbitan esters, polyoxyethylene ethers, anionice.g., sodium lauryl sulfate, sodium laurate, dialkyl sodiumsulfosuccinates, particularly bis-(2-ethylhexyl) sodium sulfosuccinate,sodium stearate, potassium stearate, and sodium oleate, cationic e.g.,benzalkonium chloride and bis-2-hydroxyethyl oleyl amine, andzwitterionic surfactants; fatty alcohols such as lauryl, cetyl, andstearyl alcohols; glyceryl esters such as the naturally occurring mono-,di-, and tri-glycerides; fatty acid esters of fatty alcohols and otheralcohols such as propylene glycol, polyethylene glycol; sucrose;polymers e.g., poloxamers such as those available under the trade namePluronic®, polyvinylpyrrolidones, glycerides e.g., triacetin, glycerylmonocaprylate, glyceryl monooleate, glyceryl monostearate; diethyleneglycol monoethyl ether; and combinations thereof.

Suitable adsorbents are selected from the group comprising silica(silicon dioxide); silicates; magnesium trisilicate; magnesium aluminiumsilicate; calcium silicate; magnesium hydroxide; talcum; crospovidone,kaolin; cyclodextrin and its derivatives; propylene glycol alginate;celluloses e.g., cellulose powder, microcrystalline cellulose, ethylcellulose, methyl cellulose, calcium carboxymethyl cellulose, sodiumcarboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,cross-linked sodium carboxymethyl cellulose; cross-linked polymethylmethacrylate; poloxamer; povidone and its derivatives; sodium starchglycolate; and combinations thereof.

Suitable complexing agents are selected from the group comprisingcrospovidone, povidone, cyclodextrin and its derivatives, andcombinations thereof.

The ion-exchange resins such as cation- and anion-exchange matrices arewell-known in the art. Few exemplary resin particles that can be usedaccording to the invention include, but are not limited to, Dowex®resins and others made by Dow Chemical; Amberlite®, Amberlyst® and otherresins made by Rohm and Haas; Indion® resins made by Ion Exchange, Ltd.(India), Diaion® resins by Mitsubishi; Type AG® and other resins byBioRad; Sephadex® and Sepharose® made by Amersham; resins by Lewatit,sold by Fluka; Toyopearl® resins by Toyo Soda; IONAC® and Whatman®resins sold by VWR; and BakerBond® resins sold by J T Baker;cholestyramine; resins having polymer backbones comprisingstyrene-divinyl benzene copolymers and having pendant ammonium ortetraalkyl ammonium functional groups, available from Rohm and Haas,Philadelphia, and sold under the tradename DUOLITE™ AP143; or anymixtures thereof.

The cores of the present invention comprising the active ingredient canbe prepared by any method known in the art, e.g.,extrusion-spheronoization, wet granulation, dry granulation, hot-meltextrusion granulation, spray drying, and spray congealing.Alternatively, the active ingredient can be layered onto an inertparticle to form the core.

Further, the active ingredient particles can be directly coated with arelease-controlling agent to form the microparticles or microcapsules.The microparticles or microcapsules can be prepared by a process ofhomogenization, solvent evaporation, coacervation phase separation,spray drying, spray congealing, polymer precipitation, or supercriticalfluid extraction.

The extended release suspension compositions of the present inventionmay further comprise one or more seal coating layers which may beapplied before and/or after the functional coating layer. The sealcoating layer may comprise of one or more film-forming polymers andcoating additives.

Examples of film-forming polymers include ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, celluloseacetate, hydroxypropyl methylcellulose phthalate, cellulose acetatephthalate, cellulose acetate trimellitate; waxes such as polyethyleneglycol; methacrylic acid polymers such as Eudragit®. Alternatively,commercially available coating compositions comprising film-formingpolymers marketed under various trade names, such as Opadry® may also beused.

The coating additives used in the present invention are selected fromthe group comprising plasticizers, opacifiers, anti-tacking agents,surfactants, coloring agents, and combinations thereof.

Suitable plasticizers are selected from the group comprising triethylcitrate, dibutylsebacate, triacetin, acetylated triacetin, tributylcitrate, glyceryl tributyrate, diacetylated monoglyceride, rapeseed oil,olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate,glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate,diethyl fumarate, dibutyl succinate, diethyl malonate, dioctylphthalate, and combinations thereof.

Suitable opacifiers are selected from the group comprising titaniumdioxide, manganese dioxide, iron oxide, silicon dioxide, andcombinations thereof.

Suitable anti-tacking agents are selected from the group comprisingsilica, calcium silicate, magnesium silicate, colloidal silicon dioxide,cornstarch, talc, stearic acid, magnesium stearate, calcium stearate,sodium stearyl fumarate, hydrogenated vegetable oil, glycerylmonostearate, and mixtures thereof.

Suitable surfactants are selected from the group comprising anionic,cationic, nonionic, or zwitterionic surfactants, or combinationsthereof. Examples of surfactants include sodium lauryl sulphate;cetrimide; polyethylene glycols; polyoxyethylene-polyoxypropylene blockcopolymers such as poloxamers; polyglycerin fatty acid esters such asdecaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fattyacid esters such as sorbitan monostearate; polyoxyethylene sorbitanfatty acid esters such as polyoxyethylene sorbitan monooleate;polyethylene glycol fatty acid esters such as polyoxyethylenemonostearate; polyoxyethylene alkyl ethers such as polyoxyethylenelauryl ether; polyoxyethylene castor oil; and mixtures thereof.

Suitable coloring agents are selected from the group consisting of FD&C(Federal Food, Drug and Cosmetic Act) approved coloring agents; naturalcoloring agents; natural juice concentrates; pigments such as ironoxide, titanium dioxide, and zinc oxide; and combinations thereof.

Coating may be performed by applying the coating composition as asolution/suspension/blend using any conventional coating technique knownin the art such as spray coating in a conventional coating pan,fluidized bed processor, dip coating, or compression coating. Thepercentage of the coating build-up shall be varied depending on therequired extended release.

Suitable solvents used for granulation or for forming a solution ordispersion for coating are selected from the group consisting of water,ethanol, methylene chloride, isopropyl alcohol, acetone, methanol, andcombinations thereof.

The extended release suspension compositions of the present inventionmay be packaged in a suitable package such as a bottle. The powder forsuspension may be packaged in a suitable package such as a bottle or asachet. Further, the sachet can be filled as a unit dose or a multidosesachet. The present invention further includes a co-package or a kitcomprising two components, wherein one package or one componentcomprises a powder for suspension and another package or anothercomponent comprises a suspension base or an aqueous vehicle.Alternatively, a dual chamber pack with two chambers can be used. Inthis case, one chamber comprises a powder for suspension and anotherchamber comprises a suspension base or an aqueous vehicle.

The invention may be further illustrated by the following examples,which are for illustrative purposes only and should not be construed aslimiting the scope of the invention in any way.

EXAMPLES Example 1

Ingredients Quantity (mg/mL) Core Metformin hydrochloride 100.00Microcrystalline cellulose spheres 90.00 Hydroxypropylmethyl cellulose5.00 Purified water q.s. Extended Release Coating Ethyl cellulose 61.42Dibutyl sebacate 6.82 Acetone q.s. Purified water q.s. Total Weight ofExtended Release Beads 263.24 mg Xylitol 450.00 Xanthan gum 1.500Microcrystalline cellulose - sodium 20.00 carboxymethyl cellulose(Avicel ® CL 611) Strawberry flavor 1.50 Vehicle Purified water q.s. to1 mL

Procedure:

-   1. Metformin hydrochloride and hydroxypropylmethyl cellulose were    dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The beads of step 2 were coated with the coating dispersion of    step 3.-   5. Xylitol, xanthan gum, microcrystalline cellulose—sodium    carboxymethyl cellulose, and strawberry flavor were mixed with the    coated beads of step 4.-   6. The mixture of step 5 was dispersed in required amount of    purified water to obtain the extended release suspension    composition.

In-Vitro Studies

In-vitro release of metformin from the extended release suspensioncomposition prepared as per Example 1 was determined by the dissolutionfor metformin using USP type II apparatus at 100 rpm, in 1000 mL ofphosphate buffer with pH 6.8 at 37° C. The results of the releasestudies are represented in Table 1.

TABLE 1 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days 0 15 30 Time (hours) Percentage of Metformin Release 2 9 9 10 334 35 37 4 56 57 57 5 69 69 68 6 76 76 75 8 85 85 84 10 90 92 89 12 9394 92

From the above data, it is clear that the extended release suspensioncomposition prepared according to Example 1 provides substantiallysimilar in-vitro metformin release for 30 days.

Example 2

Ingredients Quantity (mg/mL) Core Metformin hydrochloride 100.00Microcrystalline cellulose spheres 90.00 Hydroxypropylmethyl cellulose5.00 Purified water q.s. Extended Release Coating Ethyl cellulose 61.42Dibutyl sebacate 6.82 Acetone q.s. Purified water q.s. Total Weight ofExtended Release Beads 263.24 mg Xylitol 450.00 Xanthan gum 1.50Microcrystalline cellulose - sodium 20.00 carboxymethyl cellulose(Avicel ® CL 611) Strawberry flavor 1.50 Vehicle Purified water q.s. to1 mL

Procedure:

-   1. Metformin hydrochloride and hydroxypropylmethyl cellulose were    dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The beads of step 2 were coated with the coating dispersion of    step 3.-   5. Xylitol, xanthan gum, microcrystalline cellulose—sodium    carboxymethyl cellulose, and strawberry flavor were mixed with the    coated beads of step 4 to obtain a powder for suspension.-   6. The powder for suspension as per step 5 is reconstituted with    required amount of purified water when required to obtain the    extended release suspension composition.

Example 3

Ingredients Quantity (mg/5 mL) Core Metformin hydrochloride 500.00Microcrystalline cellulose spheres 375.00 Hydroxypropylmethyl cellulose25.00 Purified water q.s. Extended Release Coating Ethyl cellulose340.20 Dibutyl sebacate 37.80 Acetone q.s. Purified water q.s. TotalWeight of Extended Release Beads 1278.00 mg Xylitol 2250.00 Xanthan gum7.50 Microcrystalline cellulose - sodium 100.00 carboxymethyl cellulose(Avicel ® RC 591) Strawberry flavor 7.50 Vehicle Purified water q.s. to5 mL

Procedure:

-   1. Metformin hydrochloride, microcrystalline cellulose, and    hydroxypropylmethyl cellulose were sifted and mixed to obtain a    blend.-   2. The blend of step 1 was mixed with purified water to obtain a wet    mass.-   3. The wet mass of step 2 was extruded through an extruder.-   4. The extrudates of step 3 were spherionized through a spherionizer    to obtain beads.-   5. The beads of step 4 were dried.-   6. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   7. The dried beads of step 5 were coated with the coating dispersion    of step 6 to obtain a powder for suspension.-   8. Xyltiol, xanthan gum, microcrystalline cellulose—sodium    carboxymethyl cellulose, and strawberry flavor were dispersed in    purified water to obtain the vehicle.-   9. The powder for suspension of step 7 is reconstituted with the    vehicle of step 8 when required to obtain the extended release    suspension composition.

Example 4

Ingredients Quantity (mg/mL) Core Metformin hydrochloride 80.00Microcrystalline cellulose spheres 56.00 Hydroxypropylmethyl cellulose4.00 Purified water q.s. Extended Release Coating Ethyl cellulose 45.00Dibutyl sebacate 1.50 Acetone q.s. Purified water q.s. Total Weight ofExtended Release 186.50 mg Beads Metformin hydrochloride 20.00 Xylitol450.00 Microcrystalline cellulose - sodium 20.00 carboxymethyl cellulose(Avicel ® CL-611) Xanthan gum 1.50 Strawberry flavor 2.00 Sucralose 0.50Sodium benzoate 3.00 Colloidal silicon dioxide 3.50 Vehicle Purifiedwater q.s. to 1 mL

Procedure:

-   1. Metformin hydrochloride and hydroxypropylmethyl cellulose were    dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The beads of step 2 were coated with the coating dispersion of    step 3.-   5. Metformin hydrochloride, xylitol, microcrystalline    cellulose—sodium carboxymethyl cellulose, xanthan gum, strawberry    flavor, sucralose, sodium benzoate, and colloidal silicon dioxide    were mixed.-   6. The coated beads of step 4 were mixed with the mixture of step 5    to obtain a powder for suspension.-   7. The powder for suspension of step 6 is reconstituted with    required amount of purified water when required to form the extended    release suspension composition.

In-Vitro Studies

The extended release suspension composition prepared according toExample 4 was stored at room temperature for 66 days. This extendedrelease suspension was analyzed for the in-vitro dissolution at 0, 30,and 66 days using USP type II apparatus at 100 rpm, in 1000 mL ofphosphate buffer with pH 6.8 at 37° C. The results of the releasestudies are represented in Table 2.

TABLE 2 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days 0 30 66 Time (hours) Percentage of Metformin Release 0.5 27.025.6 26.3 1 30.9 31.5 31.6 2 56.9 58.3 50.9 3 74.9 72.8 70.6 4 85.6 81.781.6 5 89.1 87.7 87.4 6 94.9 90.3 92.3 8 97.7 93.5 — 10 99.4 95.3 — 12103.4 99.4 100.0 

From the above data, it is clear that the extended release suspensioncomposition prepared according to Example 4 provides substantiallysimilar in-vitro metformin release for 66 days.

The powder for suspension prepared as per Example 4 (till step 6) waskept for one month at accelerated conditions i.e., 40° C./75% R.H. Afterone month, the powder for suspension was reconstituted with requiredamount of purified water and this extended release suspensioncomposition was kept for 66 days at room temperature. The in-vitrodissolution was determined at 0, 36, and 66 days using USP type IIapparatus at 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37°C. The results of the release studies are represented in Table 3.

TABLE 3 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days After Reconstitution 0 36 66 Time (hours) Percentage ofMetformin Release 0.5 28.8 26.2 27.0 1 32.4 33 32.0 2 57.6 50.5 53.0 374.8 70.3 67.0 4 83.1 80.7 83.0 5 89.2 85.9 87.0 6 91.3 91.2 92.0 8 95.2— 95.0 10 96.6 — 97.0 12 98.6 101.3 100.0

From the above data, it is clear that the extended release powderprepared according to Example 4 stored at accelerated conditions for onemonth, upon reconstitution and storage for 66 days at room temperatureprovides substantially similar in-vitro metformin release for 66 days.The results are shown in FIG. 1.

Example 5

Ingredients Quantity (mg/mL) Core Metformin hydrochloride 80.00Microcrystalline cellulose spheres 56.00 Hydroxypropylmethyl cellulose4.00 Purified water q.s. Extended Release Coating Ethyl cellulose 50.40Dibutyl sebacate 5.60 Acetone q.s. Purified water q.s. Total Weight ofExtended Release Beads 196.00 mg Metformin hydrochloride 20.00 Xylitol450.00 Microcrystalline cellulose - sodium 20.00 carboxymethyl cellulose(Avicel ® CL-611) Xanthan gum 1.50 Strawberry flavor 2.00 Sucralose 0.50Vehicle Purified water q.s. to 1 mL

Procedure:

-   1. Metformin hydrochloride and hydroxypropylmethyl cellulose were    dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The beads of step 2 were coated with the coating dispersion of    step 3.-   5. Metformin hydrochloride, xylitol, microcrystalline    cellulose—sodium carboxymethyl cellulose, xanthan gum, strawberry    flavor, and sucralose were mixed.-   6. The coated beads of step 4 were mixed with the mixture of step 5    to form a powder for suspension.-   7. The powder for suspension of step 6 is reconstituted with    required amount of purified water when required to form the extended    release suspension composition.

In-Vitro Studies

The extended release suspension composition prepared as per Example 5was stored at room temperature for 30 days. The in-vitro dissolution wasdetermined at 0 and 30 days using USP type II apparatus at 100 rpm, in1000 mL of phosphate buffer with pH 6.8 at 37° C. The results of therelease studies are represented in Table 4.

TABLE 4 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days 0 30 Time (hours) Percentage of Metformin Release 0.5 22 24 1 3134 2 58 61 4 83 89 5 86 93 6 91 96 8 95 101 10 97 102 12 99 103

From the above data, it is clear that the extended release suspensioncomposition prepared according to Example 5 provides substantiallysimilar in-vitro metformin release for 30 days.

The powder for suspension prepared as per Example 5 (till step 6) waskept for three months at accelerated conditions i.e., 40° C./75% R.H.After three months, the powder for suspension was reconstituted withrequired amount of purified water and this extended release suspensionscomposition was kept for 32 days at room temperature. The in-vitrodissolution was determined at 0 and 32 days using USP type II apparatusat 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37° C. Theresults of the release studies are represented in Table 5.

TABLE 5 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days After Reconstitution 0 32 Time (hours) Percentage of MetforminRelease 0.5 22 26 1 33 37 2 60 66 4 85 90 5 89 94 6 92 97 8 96 101 10 98103 12 101 103

The powder for suspension prepared as per Example 5 (till step 6) waskept for six months at accelerated conditions i.e., 40° C./75% R.H.After six months, the powder for suspension was reconstituted withrequired amount of purified water and this extended release suspensionscomposition was kept for 32 days at room temperature. The in-vitrodissolution was determined at 0 and 32 days using USP type II apparatusat 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37° C. Theresults of the release studies are represented in Table 6.

TABLE 6 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days After Reconstitution 0 32 Time (hours) Percentage of MetforminRelease 0.5 24 25 1 35 34 2 63 60 4 87 86 5 91 91 6 94 94 8 97 98 10 99101 12 99 101

From the above data, it is clear that the extended release powderprepared according to Example 5 stored at accelerated conditions forthree or six months, upon reconstitution and storage for 32 days at roomtemperature provides substantially similar in-vitro metformin releasefor 32 days. The results are presented in FIG. 2.

Example 6

Ingredients Quantity (mg/mL) Core Metformin hydrochloride 80.00Microcrystalline cellulose spheres 56.00 Hydroxypropylmethyl cellulose4.00 Purified water q.s. Extended Release Coating Ethyl cellulose 61.48Dibutyl sebacate 1.52 Acetone q.s. Purified water q.s. Total Weight ofExtended Release Beads 203.00 mg Metformin hydrochloride 20.00 Xylitol450.00 Microcrystalline cellulose - sodium 20.00 carboxymethyl cellulose(Avicel ® CL- 611) Xanthan gum 1.50 Strawberry flavor 2.00 Sucralose0.50 Colloidal silicon dioxide 3.50 Vehicle Purified water q.s. to 1 mL

Procedure:

-   1. Metformin hydrochloride and hydroxypropylmethyl cellulose were    dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The beads of step 2 were coated with the coating dispersion of    step 3.-   5. Metformin hydrochloride, xylitol, microcrystalline    cellulose—sodium carboxymethyl cellulose, xanthan gum, strawberry    flavor, sucralose, and colloidal silicon dioxide were mixed.-   6. The coated beads of step 4 were mixed with the mixture of step 5    to form a powder for suspension.-   7. The powder for suspension of step 6 is reconstituted with    required amount of purified water when required to form the extended    release suspension composition.

In-Vitro Studies

The extended release suspension composition prepared as per Example 6was stored at room temperature for 30 days. The in-vitro dissolution wasdetermined at 0 and 30 days using USP type II apparatus at 100 rpm, in1000 mL of phosphate buffer with pH 6.8 at 37° C. The results of therelease studies are represented in Table 7.

TABLE 7 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days 0 30 Time (hours) Percentage of Metformin Release 0.5 20 22 1 2728 2 59 64 3 77 80 4 84 89 5 88 93 6 92 95 8 95 99 10 97 101 12 98 103

From the above in-vitro release data, it is evident that the extendedrelease suspension composition prepared according to Example 6 providesthe substantially similar in-vitro metformin release for 30 days.

The powder for suspension prepared as per Example 6 (till step 6) waskept for one month at accelerated conditions i.e., 40° C./75% R.H. Afterone month, the powder for suspension was reconstituted with requiredamount of purified water and this extended release suspensioncomposition was kept for 30 days at room temperature. The in-vitrodissolution was determined at 0 and 30 days using USP type II apparatusat 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37° C. Theresults of the release studies are represented in Table 8.

TABLE 8 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days After Reconstitution 0 30 Time (hours) Percentage of MetforminRelease 0.5 20 19 1 26 26 2 57 57 3 74 74 4 82 80 5 86 85 6 90 88 8 9291 10 94 93 12 96 94

From the above data, it is clear that the extended release powderprepared according to Example 6 stored at accelerated condition for onemonth, upon reconstitution and storage for 30 days at room temperatureprovides substantially similar in-vitro metformin release for 30 days.The results are presented in FIG. 3.

Osmolality Measurement of the Extended Release Suspension

The metformin extended release powder prepared according to the Example6 (till step 6) was reconstituted with required amount of purifiedwater. This suspension was shaken manually for at least 20 minutes. Thissuspension was then filtered and diluted with purified water and theosmolality was measured using Osmomat® 030-D.

The osmolality of the suspension base was found to be 4.112 osmol/kg ofthe suspension base on day 0.

The osmolality of the suspension base was found to be 4.328 osmol/kg ofthe suspension base on day 7.

It is evident from the above data that the osmolality of the suspensionbase of the extended release suspension composition as per Example 6remains equivalent for seven days.

Osmolality Measurement of the External Phase

The metformin hydrochloride, xylitol, microcrystalline cellulose—sodiumcarboxymethyl cellulose, xanthan gum, strawberry flavor, sucralose, andcolloidal silicon dioxide were mixed as per step 5 of Example 6. Thismixture was reconstituted with required amount of purified water. Thissuspension was then filtered and diluted with purified water, and theosmolality was measured using Osmomat® 030-D.

The osmolality of the suspension base i.e., external phase was found tobe 4.204 osmol/kg of the suspension base.

Osmolality Measurement of the Internal Phase

Various solutions having various concentrations of osmogent (sodiumchloride) were prepared as per Examples 6A-6F. The osmolalities of thesesolutions were measured using Osmomat® 030-D.

Example Example Example Example Example Example Ingredient 6A 6B 6C 6D6E 6F Sodium Chloride 30.00 60.00 120.00 180.00 240.00 300.00 (mg)Purified water q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 7.5 q.s. to 1 q.s.to 1 mL mL mL mL mL mL Osmolality 0.910 1.787 3.574* 5.361* 7.148*8.935* (osmol/kg) *Extrapolated using values of dilute solutions

The coated beads of step 4 were dispersed in different solutions as perExamples 6A-6F. These solutions were kept for seven days at roomtemperature. After seven days, each solution was analyzed by HPLC formetformin content. The results are represented in following Table 9.

TABLE 9 Effect of Osmolality on Metformin Leaching Osmolality (osmol/kg)Metformin Example of the solution Content (%) 6A 0.910 67.3 6B 1.78730.3 6C 3.574* 2.9 6D 5.361* 1.8 6E 7.148* 1.7 6F 8.935* 1.0*Extrapolated using values of dilute solutions

From the above data, it is evident that the leaching of metformin fromthe coated beads into the solution was decreasing as the osmolality ofthe solution was increasing from Examples 6A-6F. The leaching is foundto be significantly reduced from Example 6C onwards. The osmolality ofExample 6C i.e., 3.574 is considered as osmolality of the internalphase.

Osmolality Ratio 1.176 Dose Uniformity Data

The extended release suspension equivalent to 100 mL was preparedaccording to formula given in Example 6. This suspension was shakenmanually for at least 20 minutes and then ten 7.5 mL samples were takenwith a graduated syringe. The metformin content of each sample isdetermined by HPLC method [Inertsil ODS column (250×4.6 mm, 5 nm);mobile phase-buffer (pH 3.5):acetonitrile (95:5 v/v); flow rate of 1.5mL/min; UV detection at 233 nm] The results are shown in Table 10.

TABLE 10 Metformin Content (% w/w) For Each 7.5 mL of Suspension SampleMetformin content (%) for each Number 7.5 mL of suspension 1 98.6 2 97.93 96.6 4 97.2 5 99.7 6 96.4 7 95.9 8 97.3 9 98.8 10 96.9 Mean value 97.5

From the above data, it is evident that the extended release suspensioncomposition prepared as per Example 6 is homogeneous.

Assay Data

The assay for the extended release suspension composition prepared asper Example 6 was determined at 0 day and after storage at roomtemperature for 30 days. The powder for suspension prepared as perExample 6 (till step 6) was kept for one month at 40° C./75% R.H. Afterone month, the powder for suspension was reconstituted with requiredamount of purified water and then assay was determined at 0 day andafter storage at room temperature for 30 days. The assay of metforminwas determined by HPLC method [Inertsil ODS column (250×4.6 mm, 5 μm);mobile phase-buffer (pH 3.5):acetonitrile (95:5 v/v); flow rate of 1.5mL/min; UV detection at 233 nm]. The results are shown in Table 11.

TABLE 11 Assay for Metformin Assay (%) for metformin Condition 0 day 30days Initial 97.0 99.5 1 month (40° C./75% R.H) 97.4 98.9

It is evident from the above data that the extended release suspensioncomposition prepared as per Example 6 is stable.

Example 7

Ingredients Quantity (mg/mL) Core Metformin hydrochloride 80.00Microcrystalline cellulose spheres 56.00 Hydroxypropylmethyl cellulose4.00 Purified water q.s. Extended Release Coating Ethyl cellulose 68.31Dibutyl sebacate 1.69 Acetone q.s. Purified water q.s. Total Weight ofExtended Release Beads 210.00 mg Suspension base Metformin hydrochloride20.00 Xylitol 450.00 Microcrystalline cellulose - sodium 20.00carboxymethyl cellulose (Avicel ® CL-611) Xanthan gum 1.50 Methylparaben 1.80 Propyl paraben 0.20 Strawberry flavor 2.00 Sucralose 0.50Colloidal silicon dioxide 3.50 Purified water 472.00 mg

Procedure:

1. Metformin hydrochloride and hydroxypropylmethyl cellulose weredissolved in purified water.2. Microcrystalline cellulose spheres were coated with the solution ofstep 1.3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture ofacetone and purified water.4. The beads of step 2 were coated with the coating dispersion of step 3and dried to form a powder for suspension.5. Purified water was heated to dissolve methyl paraben and propylparaben.6. Metformin hydrochloride, xylitol, microcrystalline cellulose—sodiumcarboxymethyl cellulose, xanthan gum, strawberry flavor, sucralose, andcolloidal silicon dioxide were mixed in the solution of step 5 to form asuspension base.7. The powder for suspension of step 4 was prefilled in the secondchamber of a dual-chamber pack.8. The suspension base of step 7 was prefilled in a container of a firstchamber of a dual-chamber pack.9. The two chambers were assembled and the pack was activated to formthe extended release suspension composition when required.

In-Vitro Studies

The extended release suspension composition prepared as per Example 7(for a dose equivalent to 750 mg of metformin hydrochloride) was storedat room temperature for 120 days. The in-vitro dissolution wasdetermined at 0, 45, 90, and 120 days using USP type II apparatus at 100rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37° C. The results ofthe release studies are represented in Table 12.

TABLE 12 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days 0 45 90 Time (hours) Percentage of Metformin Release 120 0.5 2021 20 21 1 27 25 27 25 2 55 52 55 52 3 74 72 74 72 4 83 81 83 81 5 85 8685 86 6 87 90 87 90 8 91 94 91 94 10 93 96 93 96 12 94 97 94 97

From the above in-vitro release data, it is evident that the extendedrelease suspension composition prepared according to Example 7 providesthe substantially similar in-vitro metformin release for 120 days.

The dual-chamber pack was kept for 1 month at accelerated conditionsi.e., 40° C./75% R.H. After 1 month, the pack was activated to form anextended release suspension composition which was kept for 120 days atroom temperature. The in-vitro dissolution was determined at 0, 45, 90,and 120 days using USP type II apparatus at 100 rpm, in 1000 mL ofphosphate buffer with pH 6.8 at 37° C. The results of the releasestudies are represented in Table 13.

TABLE 13 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm) Numberof Days 0 45 90 120 Time (hours) Percentage of Metformin Release 0.5 2121 21 20 1 27 25 26 26 2 56 55 52 54 3 74 74 76 72 4 83 81 82 81 10 9696 97 94

The dual-chamber pack was kept for 3 months at accelerated conditionsi.e., 40° C./75% R.H. After 3 months, the pack was activated to form anextended release liquid composition which was kept for 45 days at roomtemperature. The in-vitro dissolution was determined at 0 and 45 daysusing USP type II apparatus at 100 rpm, in 1000 mL of phosphate bufferwith pH 6.8 at 37° C. The results of the release studies are representedin Table 14.

TABLE 14 Percentage (%) of the In-Vitro Metformin Release in USP Type IIApparatus (Media:; Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm)Number of Days 0 45 Time (hours) Percentage of Metformin Release 0.5 2121 1 26 25 2 55 53 3 75 72 4 80 80 10 95 92

From the above data, it is clear that the powder for suspension andsuspension base stored in the dual-chamber pack of the instant inventionat accelerated conditions for 1 month and 3 months, upon activation ofthe pack forms extended release suspension compositions which whenstored for 120 days and 45 days respectively at room temperatureprovides substantially similar in-vitro metformin release.

Stability Data

The related substances for the extended release suspension compositionprepared as per Example 7 were determined at 0 day and after storage atroom temperature for 45 and 120 days. The powder for suspension andsuspension base was stored in the dual-chamber pack for one month andfor three months at 40° C./75% R.H. After one month or three months, thepack was activated to form an extended release suspension compositionand then related substances were determined at 0 day and after storageat room temperature for 45 days and 120 days.

The assay of metformin was determined by HPLC method. The results areshown in Table 15.

TABLE 15 Stability Data for Metformin 1 month 3 month Related Initial(40° C./75% R.H) (40° C./75% R.H) Substances 0 45 120 0 45 120 0 45 (%w/w) day days days day days days day days Cyanoguainidine BLQ 0.0010.00072 0.001 0.001 0.001 0.001 0.001 Highest unknown 0.05 0.05 0.040.05 0.04 0.04 0.05 0.04 impurity Total impurities 0.05 0.05 0.04 0.050.04 0.04 0.09 0.04 *BLQ: Below limit of Quantification

Osmolality of the suspension base: 3.960 osmol/Kg of the suspension baseas measured by using Osmomat® 030-D.

Viscosity of the suspension base: 2880 cps as measured by usingBrookfield Viscometer using a #2 spindle rotating at 5 rpm at 25° C.

Example 8 Preparation of Extended Release Beads

Ingredients Quantity (mg) Core Guanfacine hydrochloride 1.15Microcrystalline cellulose spheres 4.00 Hydroxypropylmethyl cellulose30.00 Mannitol 10.00 Purified Water q.s. Extended Release Coating Ethylcellulose 14.22 Dibutyl sebacate 1.58 Acetone q.s. Purified Water q.s.Total Weight of Extended Release Beads 60.95 mg

Procedure:

-   1. Guanfacine hydrochloride and hydroxypropylmethyl cellulose were    dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The beads of step 2 were coated with the coating dispersion of    step 3.

Various solutions having various concentrations of osmogent (sodiumchloride) were prepared as per Examples 8A-7D. The osmolalities of thesesolutions were measured using Osmomat® 030-D.

Example Example Example Example Ingredient 8A 8B 8C 8D Sodium Chloride(mg) 30.00 60.00 120.00 180.00 Purified water q.s. to 1 q.s. to 1 q.s.to 1 q.s. to 1 mL mL mL mL Osmolality (osmol/kg) 0.910 1.787 3.574*5.361* *Extrapolated using values of dilute solutions Sodium chloridewas dissolved in purified water as per Examples8A-8D. The osmolality ofthese solutions were measured using Osmomat ® 030-D.

The coated beads of step 4 were dispersed in different suspension basesas per Examples 8A-8D. These suspensions were kept for seven days atroom temperature. After seven days, each suspension was filtered anddiluted with purified water. These were then analyzed by using HPLC forguanfacine content. The results are represented in following Table 16.

TABLE 16 Effect of Osmolality on Guanfacine Leaching Osmolality(osmol/kg) of Guanfacine Example the solution Content (%) 8A 0.910 69.808B 1.787 8.90 8C 3.574* 1.30 8D 5.361* 0.30 *Extrapolated using valuesof dilute solutions

From the above data, it is evident that the leaching of guanfacine fromthe coated beads into the solution was decreasing as the osmolality ofthe solution was increasing from Examples 8A-8D.

Example 9

Ingredients Quantity (mg/mL) Core Valacyclovir hydrochloride (equivalentto 111.24 100 mg of valacyclovir) Microcrystalline cellulose spheres70.00 Hydroxypropylmethyl cellulose 5.56 Purified water q.s. ExtendedRelease Coating Ethyl cellulose 45.58 Dibutyl sebacate 1.13 Acetone q.s.Purified water q.s. Total Weight of Extended Release Beads 233.51 mgXylitol 450.00 Xanthan gum 1.50 Microcrystalline cellulose - sodium20.00 carboxymethyl cellulose (Avicel ® CL 611) Strawberry flavor 1.50Vehicle Purified water q.s to 1.0 ml

Procedure:

-   1. Valacyclovir hydrochloride and hydroxypropylmethyl cellulose are    dissolved in purified water.-   2. Microcrystalline cellulose spheres are coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate are dispersed in a mixture    of acetone and purified water.-   4. The beads of step 2 are coated with the coating dispersion of    step 3.-   5. Xylitol, xanthan gum, microcrystalline cellulose—sodium    carboxymethyl cellulose, strawberry flavor are mixed.-   6. The coated beads of step 4 are mixed with the mixture of step 5    to form a powder for suspension.-   7. The powder for suspension of step 6 is reconstituted with    required amount of purified water when required to form the extended    release suspension composition.

Example 10

Ingredients Quantity (mg/5 mL) Core Amoxicillin 1000.00 Microcrystallinecellulose spheres 200.00 Polyvinylpyrrolidone 60.00 Purified water q.s.Extended Release Coating Ethyl cellulose 500.00 Dibutyl sebacate 50.00Acetone q.s. Purified water q.s. Total Weight of Extended Release Beads1810.00 mg Clavulanic acid 62.50 Lemon flavor 1.50 Xylitol 450.00Microcrystalline cellulose - sodium 20.00 carboxymethyl cellulose(Avicel ® CL 611) Strawberry flavor 1.50 Vehicle Purified water q.s to5.0 mL

Procedure:

-   1. Amoxicillin and polyvinylpyrrolidone are dispersed in purified    water.-   2. Microcrystalline cellulose spheres are coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate are dispersed in a mixture    of acetone and purified water.-   4. The beads of step 2 are coated with the coating dispersion of    step 3.-   5. Clavulanic acid, lemon flavor, xylitol, microcrystalline    cellulose—sodium carboxymethyl cellulose, strawberry flavor are    mixed.-   6. The coated beads of step 4 are mixed with the mixture of step 5    to form a powder for suspension.-   7. The powder for suspension of step 6 is reconstituted with    required amount of purified water when required to form the extended    release suspension composition.

Example 11

Ingredients Quantity (mg/mL) Core Esomeprazole magnesium 44.50 Non-pareil seeds 100.00 Hydroxypropyl cellulose 20.00 Crospovidone 30.00Purified water q.s. Seal Coating Hydroxypropyl methyl cellulose 14.98Polyethylene glycol 1.49 Talc 2.98 Purified water q.s. Extended ReleaseCoating Methacrylic acid copolymer dispersion 33.47 (Eudragit ® L30D-55) Polyethylene glycol 3.35 Talc 12.72 Titanium dioxide 3.95 Purifiedwater q.s. Lubrication Talc 12.56 Total Weight of Extended Release Beads280.00 mg Xylitol 450.00 Vehicle Purified water q.s to 1.0 mL

Procedure:

-   1. Esomeprazole magnesium, hydroxypropyl cellulose, crospovidone are    dispersed in purified water and is stirred to get form a dispersion.-   2. The non-pareil seeds are coated with dispersion of step 1.-   3. The hydroxypropylmethyl cellulose, polyethylene glycol, and talc    are dispersed in purified water to get a dispersion.-   4. The coated pellets of step 2 are coated with the dispersion of    step 3.-   5. The polyethylene glycol, methacrylic acid copolymer dispersion,    talc, and titanium dioxide are dispersed in purified water to get a    dispersion.-   6. The coated pellets of step 4 are coated with the dispersion of    step 5.-   7. The coated pellets of step 6 are lubricated with talc.-   8. The lubricated pellets of step 7 are mixed with xylitol to obtain    a powder for suspension.-   9. The powder for suspension of step 8 is reconstituted with    required amount of purified water when required to form the extended    release suspension composition.

1-14. (canceled)
 15. A stable extended release reconstituted powder forsuspension composition comprising multiple coated cores of an activeingredient comprising an active ingredient layered onto an inertparticle to form the core, a coating layer over said core comprising oneor more release-controlling agents to form coated cores having averagediameter ranging from about 150 μm to about 500 μm, wherein uponreconstitution with a suspension base, the composition is homogeneousand ensures substantially similar in-vitro dissolution release profileof the active ingredient upon storage of the composition uponreconstitution for at least seven days and wherein the suspension baseused for reconstitution of the composition is characterized by having aviscosity in a range of about 500 cps to about 15,000 cps.
 16. Thestable extended release reconstituted powder for suspension compositionof claim 15, wherein the inert particle is selected from the groupconsisting of a non-pareil seed, a microcrystalline cellulose sphere, adibasic calcium phosphate bead, a mannitol bead, a silica bead, atartaric acid pellet, and a wax based pellet.
 17. The stable extendedrelease reconstituted powder for suspension composition of claim 15,wherein the suspension base comprises: (i) a suspending agent; (ii) anosmogent; and (iii) an aqueous vehicle.
 18. The stable extended releasereconstituted powder for suspension composition of claim 17, wherein thesuspending agent is selected from group consisting of cellulosederivatives; carbomers; gums; pectin; dextran; gelatin; polyethyleneglycols; polyvinyl compounds; sugar alcohols; and mixtures thereof. 19.The stable extended release reconstituted powder for suspensioncomposition of claim 15, wherein the release-controlling agent isselected from the group consisting of a pH-dependent release-controllingagent, a pH-independent release-controlling agent, and mixtures thereof.20. The stable extended release reconstituted powder for suspensioncomposition of claim 15, wherein the pH-dependent release-controllingagent is selected from the group consisting of acrylic copolymers;cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkylcellulose phthalates; hydroxyalkyl cellulose acetate succinates; vinylacetate phthalates; vinyl acetate succinate; cellulose acetatetrimelliate; polyvinyl derivatives; zein; shellac; and mixtures thereof.21. The stable extended release reconstituted powder for suspensioncomposition of claim 15, wherein the pH-independent release-controllingagent is selected from the group consisting of cellulosic polymers;acrylic copolymers; cellulose acetate; polyethylene derivatives;polyvinyl alcohol; polyvinyl acetate; gums; lipids; fatty acids or theirsalts/derivatives; a mixture of polyvinyl acetate and polyvinylpyrrolidone; and mixtures thereof.
 22. The stable extended releasereconstituted powder for suspension composition of claim 15, wherein theactive ingredient is selected from the group consisting of metformin,acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide,glimepride, glipizide, gliclazide, chloropropamide, tolbutamide,phenformin, aloglitin, sitagliptin, linagliptin, saxagliptin,rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone,darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar,peliglitazar, tesaglitazar, canagliflozin, dapagliflozin, remogliflozin,sergliflozin, verapamil, albuterol, salmeterol, acebutolol, sotalol,penicillamine, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin,moxifloxacin, cefpodoxime, tetracycline, demeclocycline hydrochloride,amoxicillin, clavulanate potassium, azithromycin, losartan, irbesartan,eprosartan, valsartan, diltiazem, isosorbide mononitrate, ranolazine,propafenone, hydroxyurea, hydrocodone, delavirdine, pentosanpolysulfate, abacavir, amantadine, acyclovir, ganciclovir, valacyclovir,valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine,didanosine, zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen,propoxyphene, cimetidine, ranitidine, albendazole, mebendazole,thiobendazole, pyrazinamide, praziquantel, chlorpromazine, sumatriptan,bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride,niacin, tocainide, quetiapine, fexofenadine, sertraline,chlorpheniramine, rifampin, methenamine, nefazodone, modafinil,metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate,simethicone, methyldopa, chlorthiazide, metyrosine, procainamide,entacapone, metoprolol, propanolol hydrochloride, chlorzoxazone,tolmetin, tramadol, bepridil, phenytoin, gabapentin, fluconazole,terbinafine, atorvastatin, doxepine, rifabutin, mesalamine, etidronate,nitrofurantoin, choline magnesium trisalicylate, theophylline,nizatidine, methocarbamol, mycophenolate mofetil, tolcapone,ticlopidine, capecitabine, orlistat, colsevelam, meperidine,hydroxychloroquine, guaifenesin, guanfacine, amiodarone, quinidine,atomoxetine, felbamate, pseudoephedrine, carisoprodol, venlafaxine,etodolac, chondrotin, lansoprazole, pantoprazole, esomeprazole,dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate,valproic acid or its salts, divalproex, topiramate, carbamazepine,oxcarbazepine, and isotretinoin.
 23. The stable extended releasereconstituted powder for suspension composition of claim 15, wherein thesuspension base further comprises one or more pharmaceuticallyacceptable excipients selected from the group consisting of anti-cakingagents, wetting agents, preservatives, buffering agents, flavoringagents, anti-oxidants, chelating agents, solubility enhancing agents, pHmodifying agents, adsorbents, complexing agents, and combinationsthereof.